Angiotensin II type 1 receptor antagonist (losartan) down-regulates transforming growth factor-beta in experimental acute pyelonephritis

Purpose: To study the effect of an angiotensin II type 1 receptor antagonis t, losartan, on cytokine expression, kidney growth and renal scarring in ex perimental acute pyelonephritis. Materials and Methods: Female Bki NMRI mice, 8 weeks old were infected with E. coli CFT 073 via the urethra. Mice were divided into four groups; eithe r left untreated; or treated with NaCl 0.9%; or an angiotensin II type 1 re ceptor antagonist, losartan, in doses of 1 mg. or 40 mg./kg. body weight. T he treatment was given daily i.p. for 48 hours, 3 weeks or 8 weeks respecti vely. Kidneys were weighed and sectioned for histo-pathology and in situ hy bridization for mRNA of IL-1 beta, TNF-alpha, IL-4, IL-6, IL-10, IL-12, TGF -beta and IFN-gamma. Homogenized kidneys were used for EIA of TGF-beta and bacterial growth. Results: The mRNA expression of the studied cytokines generally peaked at 4 8 hours in all four groups. In animals treated with losartan, kidney TGF-be ta, IFN-gamma and IL-6 decreased significantly at 3 and 8 weeks as compared with controls, untreated or those treated with NaCl, (p <0.005 respectivel y). Infection was associated with a declining kidney weight, also in the pr esence of losartan. A 50% reduction of the spread of renal scarring was obs erved in the losartan treated group, but this did however not reach signifi cance. The proportion of kidneys showing bacterial growth was not influence d by losartan although in these kidneys the mean bacterial counts at 3 week s were significantly higher in the losartan treated mice (p <0.006). Conclusions: Losartan is associated with downregulation of TGF-beta, TFN-ga mma and IL-6 and may, in combination with antimicrobial therapy, reduce the risk of cortical renal scarring in recurrent acute pyelonephritis in infan ts.